Human onchocerciasis is a serious neglected tropical disease caused by Onchocerca volvulus (Ov) and an important cause of blindness and chronic disability in the developing world. Through mass drug administration of ivermectin, onchocerciasis has been recognized by the WHO as a potential candidate for global elimination. However, formidable technical and logistical obstacles must be overcome before the goal of elimination in Africa can be attained. In addition to difficulties of compliance in this region, evidence is building for the existence of Onchocerca resistance to the drug ivermectin, which is at present the only drug used for the mass treatment of this population. Therefore, additional tools are critically needed and include the need for a vaccine against onchocerciasis to complement the present control measures and thus potentially eliminate this infection from humans. We envision that the Onchocerca vaccine will be indicated as a product to protect vulnerable populations living in endemic areas against infection and disease (skin disease and blindness). Reduction in adult worm burden will reduce the number of microfilariae produced by the adult female worms and thus pathology and potentially also the rates of transmission within these endemic regions. Importantly, protective immunity against Ov larvae has now been definitively demonstrated in humans, cattle and mice, thereby proving the conceptual underpinnings that a vaccine can be produced against this infection. Using an innovative selection strategy designed for this project we now have in hand a portfolio of eight protective antigens that have been proven to function as vaccines not only in the Ov - mouse model but also in other nematode animal models such as lymphatic filariae and intestinal worms using the species specific homologous vaccine antigens. The proposed studies will expand and refine the existing research foundations on these antigens. Our approach is to move forward from the completed antigen discovery stage and initiate the required preclinical research and development process that will result, through a robust screening process, with the discovery of the best 2 recombinant Ov vaccine antigens with the highest probability for success at inducing protective immunity in humans. The vaccine will target the Ov larvae, known to be vulnerable to host immunological attack. This will be accomplished through three specific aims: 1) To select 4 Onchocerca vaccine antigens from the portfolio of 8 based on their protective efficacy in two laboratory animal models; 2) To determine the maximum parasite killing potential of the 4 selected antigens using vaccine optimization and then select the 2 best vaccine antigen/adjuvant formulations; and 3) To establish mechanisms and immune correlates associated with protective immunity induced by the 2 most efficacious vaccine antigen/adjuvant formulations. Our proposed strategy will result in the identification of selected Ov vaccine antigens that could be moved into product development and manufacturing with the ultimate goal of clinical development and testing of a first-generation recombinant Onchocerca vaccine.